161 results on '"Elie Serge Zafrani"'
Search Results
2. Contribution of the ELFG test in algorithms of non-invasive markers towards the diagnosis of significant fibrosis in chronic hepatitis C.
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Jean-Pierre Zarski, Nathalie Sturm, Jérôme Guechot, Elie-Serge Zafrani, Michel Vaubourdolle, Sophie Thoret, Jennifer Margier, Sandra David-Tchouda, and Jean-Luc Bosson
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Medicine ,Science - Abstract
BACKGROUND AND AIMS: We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests. PATIENTS AND METHODS: We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn's, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy. RESULTS: In "intention to diagnose" the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In "per-analysis" Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64-69%). CONCLUSION: The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.
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- 2013
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3. DNA degrades during storage in formalin-fixed and paraffin-embedded tissue blocks
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Jean-Christophe Fournet, Jeanne Tran Van Nhieu, Elie-Serge Zafrani, Alice Boyez, J. Moroch, Cyrielle Robe, Karen Leroy, Yves Allory, Odette Georges, Alice Guyard, and Anaïs Pujals
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0301 basic medicine ,Tissue Fixation ,Biology ,Real-Time Polymerase Chain Reaction ,medicine.disease_cause ,Pathology and Forensic Medicine ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,0302 clinical medicine ,Formaldehyde ,Multiplex polymerase chain reaction ,Biopsy ,medicine ,Humans ,Molecular Biology ,Retrospective Studies ,Paraffin Embedding ,medicine.diagnostic_test ,Carcinoma ,High-Throughput Nucleotide Sequencing ,DNA ,Cell Biology ,General Medicine ,Molecular biology ,DNA extraction ,030104 developmental biology ,Real-time polymerase chain reaction ,chemistry ,030220 oncology & carcinogenesis ,DNA fragmentation ,KRAS - Abstract
Formalin-fixed paraffin-embedded (FFPE) tissue blocks are widely used to identify clinically actionable molecular alterations or perform retrospective molecular studies. Our goal was to quantify degradation of DNA occurring during mid to long-term storage of samples in usual conditions. We selected 46 FFPE samples of surgically resected carcinomas of lung, colon, and urothelial tract, of which DNA had been previously extracted. We performed a second DNA extraction on the same blocks under identical conditions after a median period of storage of 5.5 years. Quantitation of DNA by fluorimetry showed a 53% decrease in DNA quantity after storage. Quantitative PCR (qPCR) targeting KRAS exon 2 showed delayed amplification of DNA extracted after storage in all samples but one. The qPCR/fluorimetry quantification ratio decreased from 56 to 15% after storage (p
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- 2017
4. Germline and somatic DICER1 mutations in familial and sporadic liver tumors
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Julien Calderaro, Olivier Seror, Stefano Caruso, Elie-Serge Zafrani, Eric Letouzé, Jean-Charles Nault, Gabrielle Couchy, Paulette Bioulac-Sage, Sandrine Imbeaud, Jessica Zucman-Rossi, Anais Boulai, and Alain Luciani
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Adult ,Male ,Ribonuclease III ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Somatic cell ,DNA Mutational Analysis ,Mutation, Missense ,Pleuropulmonary blastoma ,Biology ,medicine.disease_cause ,Germline ,DEAD-box RNA Helicases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Neoplasm ,Germ-Line Mutation ,beta Catenin ,Exome sequencing ,Aged ,Aged, 80 and over ,Mutation ,Hepatology ,Liver Neoplasms ,Middle Aged ,HCCS ,medicine.disease ,Pedigree ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,Neoplasm Recurrence, Local ,Transcriptome - Abstract
Background & Aims Growing evidence suggests that genetic predisposition significantly increases the risk of hepatocellular carcinoma (HCC), independently from the presence of other risk factors. Here, we report a novel germline DICER1 mutation associated with familial recurrent liver tumors. We then aimed to investigate the contribution of constitutional and somatic DICER1 mutations on HCC occurrence. Methods We investigated two individuals of a single family that developed recurrent well-differentiated hepatocellular tumors over the years. Histological slides from surgically resected tumors were reviewed. Exome sequencing was performed on constitutional DNA from circulating lymphocytes in both patients. The presence of somatic DICER1 mutations was analyzed in 243 liver tumors. MicroRNA (miRNA) sequencing was performed in 50 liver tumors to identify groups of tumors with similar profiles and differentially expressed miRNAs (DEMs). Results A pathological study identified hepatocellular adenomas and well-differentiated carcinomas in both patients. Tumors exhibited Wnt/β-catenin pathway activation, with strong and diffuse glutamine synthetase expression. Interestingly, non-tumor liver tissues showed abnormal liver zonation as previously reported in Dicer1 knockout mouse livers. Screening for DICER1 mutations in 243 sporadic liver tumors identified six tumors with somatic DICER1 mutations. In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations ( p =0.03). miRNA profiling identified a specific expression profile in DICER1 -mutated tumors with a decreased expression of mature miRNAs compared to the other samples. Among the DEMs, downregulation of let-7a and miR-365b was closely related to DICER1 mutations. Conclusions Our results highlight the role of DICER1 mutations in liver carcinogenesis in a specific subtype of familial and sporadic hepatocellular carcinomas associated with β-catenin activation. Lay summary DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor. Here, we described familial HCC associated with a novel DICER1 germline mutation and altered liver zonation. Familial and sporadic HCCs carrying DICER1 mutations are associated with CTNNB1 mutation and characterized by a reduced expression of specific mature miRNAs.
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- 2017
5. Impact of hepatobiliary phase liver MRI versus Contrast-Enhanced Ultrasound after an inconclusive extracellular gadolinium-based contrast-enhanced MRI for the diagnosis of benign hepatocellular tumors
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Laurence Baranes, Frederic Pigneur, Elie Serge Zafrani, Julien Calderaro, Charlotte Costentin, Daniel Azoulay, Vincent Roche, Lambros Tselikas, Alain Rahmouni, Marion Roux, Alexis Laurent, Edouard Herin, Alain Luciani, and Ariane Mallat
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Adenoma ,Adult ,Male ,medicine.medical_specialty ,Urology ,Gadolinium ,Contrast Media ,chemistry.chemical_element ,Sensitivity and Specificity ,030218 nuclear medicine & medical imaging ,Lesion ,03 medical and health sciences ,Meglumine ,0302 clinical medicine ,Internal medicine ,Biopsy ,Organometallic Compounds ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Retrospective Studies ,Ultrasonography ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Liver Neoplasms ,Ultrasound ,Gastroenterology ,Focal nodular hyperplasia ,Middle Aged ,Hepatocellular adenoma ,Hepatology ,medicine.disease ,Magnetic Resonance Imaging ,chemistry ,Focal Nodular Hyperplasia ,Female ,030211 gastroenterology & hepatology ,Radiology ,medicine.symptom ,business ,Contrast-enhanced ultrasound - Abstract
To compare the added values of hepatobiliary phase (HBP) MRI and contrast-enhanced ultrasound (CEUS) in addition to inconclusive extracellular gadolinium-based contrast-enhanced MRI (CE-MRI) to characterize benign hepatocellular tumors (BHT). Eighty-three BHT-46 focal nodular hyperplasia (FNH) and 37 hepatocellular adenomas (HCA)-with inconclusive CE-MRI in 54 patients (43 women and 11 men, mean age 42 years old ± 14.8) were retrospectively analyzed. All patients underwent both HBP-MRI and CEUS. Two radiologists independently reviewed 2 sets of images, SET-1: CE-MRI and HBP-MRI; SET-2: CE-MRI and CEUS, and classified lesions as “definite FNH,” “possible FNH,” or “definitely not FNH.” Sensitivity (Se) and specificity (Spe) were compared between the two sets; subgroup analyses according to the lesion’s size were performed. Regardless of lesion size, the respective Se and Spe of both datasets were not statistically different (95.7 and 100% vs. 76.1 and 94.6% for set-1 and -2 respectively; p = 0.18). For lesions larger than 35 mm, although both sets had similar specificity (100%), sensitivity was higher for SET-1 (100% vs. 40%); p = 0.04. Tumor classifications using SET-1 and SET-2 could have changed patient management in 35/54 (64.8%) and 33/54 (61.1%) of all patients, respectively. HBP-MRI or CEUS should be performed after an inconclusive CE-MRI. Both can change patient management by avoiding unnecessary biopsy or surveillance. The use of HBP-MRI should be advocated over CEUS in larger (>35 mm) lesions.
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- 2016
6. Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis
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Dalila Mehdaoui, Charles Balabaud, Gabrielle Couchy, Alain Luciani, Elie Serge Zafrani, Jean C Nault, Paulette Bioulac-Sage, Jessica Zucman-Rossi, Julien Calderaro, Daniel Azoulay, and Marie-Christine Saint-Paul
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Adult ,Liver Cirrhosis ,Male ,STAT3 Transcription Factor ,Pathology ,medicine.medical_specialty ,Cirrhosis ,Adenoma ,Biology ,Gene mutation ,Chronic liver disease ,Adenoma, Liver Cell ,Pathology and Forensic Medicine ,End Stage Liver Disease ,03 medical and health sciences ,0302 clinical medicine ,Chromogranins ,Cytokine Receptor gp130 ,GTP-Binding Protein alpha Subunits, Gs ,medicine ,GNAS complex locus ,Humans ,Hepatocyte Nuclear Factor 1-alpha ,Serum amyloid A ,Promoter Regions, Genetic ,Telomerase ,beta Catenin ,Liver Neoplasms ,Middle Aged ,Hepatocellular adenoma ,medicine.disease ,HNF1A ,Liver ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,030211 gastroenterology & hepatology - Abstract
Hepatocellular adenoma is considered to occur exclusively in non-fibrotic livers. It is a heterogeneous entity and a molecular classification is now widely accepted. The most frequent hepatocellular adenoma subtype, namely inflammatory adenoma, harbor somatic activating mutations of genes involved in the interleukin-6 pathway that lead to high C-reactive protein and serum amyloid A expression. The aim of our study was to investigate a series of benign hepatocellular neoplasms developed on cirrhotic livers and characterized by an unequivocal histological diagnosis. We performed a clinical, pathological, and molecular study of 10 benign hepatocellular neoplasms developed in three patients with cirrhosis. Markers allowing hepatocellular adenoma classification were assessed by quantitative real-time PCR and immunohistochemistry. Samples were sequenced for CTNNB1, HNF1A, IL6ST, GNAS, STAT3, and TERT (promoter) mutations. A control series of 32 classical macronodules developed in cirrhosis related to various etiologies was screened by immunohistochemistry and gene sequencing. The three patients had cirrhosis related to metabolic syndrome and/or alcohol intake; two had a single tumor, while the third developed more than 30 lesions. Microscopic examination showed well-differentiated neoplasms sharing features with inflammatory adenoma including inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels. Sequencing revealed classical hotspot somatic mutations (IL6ST, n=8; STAT3, n=1; and GNAS, n=1) known to be responsible for IL-6/JAK/STAT pathway activation. Two classical high-grade macronodules demonstrated high serum amyloid A and/or C-reactive protein expression, without gene mutations. Altogether, our findings support the existence of rare inflammatory adenoma developed in cirrhosis.
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- 2016
7. Systemic AA amyloidosis caused by inflammatory hepatocellular adenoma
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Oriol Bestard, Jessica Zucman-Rossi, Julien Calderaro, Dominique Franco, Jean-Charles Nault, Victor Renault, Michel Moutschen, Quentin Bayard, Eric Letouzé, Jean-François Deleuze, Anais Boulai, Elie-Serge Zafrani, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Bellvitge University Hospital, Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Henri Mondor University Hospital, Université de Liège, Supported by the Institut National du Cancer with the International Cancer Genome Consortium (ICGC Liver Cancer–France project), INSERM with the 'Cancer et Environnement' (plan Cancer) and Heterogeneity of Colorectal and Liver Cancer (HETCOLI) projects (Tumor Heterogeneity and Ecosystem program), the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology Investissement d’Avenir, Coup d’Elan de la Fondation Bettencourt–Schueller, the Site de Recherche Intégrée sur le Cancer–Cancer Research and Personalized Medicine (SIRIC CARPEM), Fondation Mérieux, Cancéropôle Ile de France (exhauTrans project), and Instituto de Salud Carlos III (Spanish competitive grants FIS PI16/01321 and INT15/00112, to Dr. Bestard) through the European Regional Development Fund for research., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)
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Serum ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Adenoma ,Liver cytology ,[SDV]Life Sciences [q-bio] ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Fetge ,AA amyloidosis ,Gene expression ,medicine ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Sèrum ,Proteins ,General Medicine ,Amyloidosis ,Hepatocellular adenoma ,medicine.disease ,digestive system diseases ,3. Good health ,stomatognathic diseases ,Liver ,030220 oncology & carcinogenesis ,Inflammatory Hepatocellular Adenoma ,Amiloïdosi ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Liver pathology ,Proteïnes - Abstract
To the Editor: Amyloid A (AA) systemic amyloidosis is a complication of chronic inflammatory diseases that is caused by the deposition of insoluble aggregates of cleaved N-terminal fragments of serum amyloid A (SAA) protein in tissues and organs throughout the body. Under physiologic conditions, SAA protein is produced by hepatocytes during the acute inflammatory phase in response to various cytokines such as interleukin-6. SAA is also overexpressed by neoplastic hepatocytes in inflammatory hepatocellular adenomas, a specific molecular subtype of benign liver tumors.
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- 2018
8. Differentiation of focal nodular hyperplasia from hepatocellular adenoma: Role of the quantitative analysis of gadobenate dimeglumine-enhanced hepatobiliary phase MRI
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Alain Luciani, Laurence Baranes, J. Calderaro, Alain Rahmouni, Daniel Azoulay, Elie-Serge Zafrani, Alexis Laurent, Thomas Decaens, Lambros Tselikas, Frederic Pigneur, M. Chiaradia, Marion Roux, Ariane Mallat, and Charlotte Costentin
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medicine.medical_specialty ,medicine.diagnostic_test ,Receiver operating characteristic ,business.industry ,Focal nodular hyperplasia ,Magnetic resonance imaging ,Hepatocellular adenoma ,medicine.disease ,Lesion ,Hepatobiliary phase ,Medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,medicine.symptom ,business ,Nuclear medicine ,Quantitative analysis (chemistry) ,GADOBENATE DIMEGLUMINE - Abstract
Purpose To determine the value of quantitative analysis of the hepatobiliary phase (HBP) in gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) to differentiate focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). Materials and Methods Thirty-eight patients bearing 67 lesions (40 FNH; 27 HCA) were retrospectively included in this Institutional Review Board-approved study. The same volumetric interpolated breath-hold examination (VIBE) T1-weighted sequences were performed before and after contrast injection on a 1.5T MRI, with HBP images acquired with a mean delay of 80 minutes (range 60–120 min). After a visual assessment of lesions enhancement (qualitative HBP analysis), the HBP signal intensity ratio (SIR) and the lesion-to-liver contrast enhancement ratio (LLCER) were calculated for each lesion by two observers (Mann-Whitney test). The sensitivities, specificities (receiver operating characteristic [ROC] curve analysis) and interobserver correlation (intraclass coefficient, ICC) of quantitative HBP analysis were determined. Results All FNH and 44.4% of HCA appeared hyper- or isointense relative to the adjacent liver on qualitative HBP analysis. The mean SIR (P
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- 2015
9. BRAF V600E mutational status in bile duct adenomas and hamartomas
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Elie Serge Zafrani, Claire Castain, Julien Calderaro, Paulette Bioulac-Sage, Cécile Charpy, and Anaïs Pujals
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Male ,Proto-Oncogene Proteins B-raf ,Pathology ,medicine.medical_specialty ,Histology ,Hamartoma ,DNA Mutational Analysis ,Pathology and Forensic Medicine ,law.invention ,Adenoma, Bile Duct ,law ,Mutant protein ,Biomarkers, Tumor ,medicine ,Humans ,neoplasms ,Polymerase chain reaction ,Bile Duct Adenoma ,Aged ,Aged, 80 and over ,Bile duct ,business.industry ,General Medicine ,Middle Aged ,Bile duct hamartoma ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,Ductal Plate Malformation ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Female ,business ,V600E - Abstract
Aims Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH. Methods and results Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH. Conclusion Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations.
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- 2015
10. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver
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Alexandra Bizy, Fouad Lafdil, Nabila Hamdaoui, Elie-Serge Zafrani, Adrien Guillot, Keve Zoltani, Rachid Souktani, Ariane Mallat, and Sophie Lotersztajn
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medicine.medical_specialty ,Hepatology ,biology ,medicine.medical_treatment ,Interleukin ,Proinflammatory cytokine ,Endocrinology ,Cytokine ,Internal medicine ,medicine ,biology.protein ,Cannabinoid receptor type 2 ,STAT protein ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,Receptor ,STAT5 - Abstract
Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2−/− mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2−/− BDL mice. In vitro, differentiation of CD4+ naive T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17-induced proinflammatory gene expression. Conclusion: These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production. (Hepatology 2014;58:296–306)
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- 2013
11. Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship With clinical and pathological features
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Elie-Serge Zafrani, Fouad Lafdil, Benoit Rousseau, Charlotte Costentin, Alexis Laurent, Cécile Charpy, Giuliana Amaddeo, Jean-Michel Pawlotsky, Alain Luciani, Julien Calderaro, Daniel Azoulay, and Marion Mercey
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0301 basic medicine ,Sorafenib ,Male ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Biology ,B7-H1 Antigen ,03 medical and health sciences ,Cytokeratin ,0302 clinical medicine ,PD-L1 ,Carcinoma ,medicine ,Biomarkers, Tumor ,Humans ,Tumor microenvironment ,Hepatology ,Liver Neoplasms ,Middle Aged ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,biology.protein ,Biomarker (medicine) ,Female ,medicine.drug - Abstract
The prognosis of hepatocellular carcinoma (HCC) remains poor, with only one third of patients eligible for curative treatments and very limited survival benefits with the use of sorafenib, the current standard of care for advanced disease. Recently, agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) immune checkpoint were shown to display impressive antitumor activity in various solid or hematological malignancies, including HCC. PD-L1 immunohistochemical expression is thought to represent a biomarker predictive of drug sensitivity. Here, we investigated PD-L1 expression in a series of 217 HCCs and correlated our results with clinical and histological features and immunohistochemical markers (PD-1, cytokeratin 19, glutamine synthetase, and β-catenin expression). PD-L1 expression by neoplastic cells was significantly associated with common markers of tumor aggressiveness (high serum alpha-fetoprotein levels, P = 0.038; satellite nodules, P
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- 2016
12. Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice
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Arthur Brouillet, Dominique Couchie, Marie-Noële Chobert, Elie-Serge Zafrani, P. Mavier, Y. Laperche, and Agnès Fourcot
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Male ,Time Factors ,Physiology ,Inflammation ,Thioacetamide ,Biology ,Liver Cirrhosis, Experimental ,Hepatitis ,Mice ,Fibrosis ,Proto-Oncogene Proteins ,Physiology (medical) ,medicine ,Animals ,Macrophage ,Ethionine ,Myofibroblasts ,Carbon Tetrachloride ,Cell Proliferation ,Mice, Knockout ,Innate immune system ,Hepatology ,GAS6 ,Stem Cells ,Regeneration (biology) ,Gastroenterology ,Receptor Protein-Tyrosine Kinases ,Lipid Metabolism ,medicine.disease ,Axl Receptor Tyrosine Kinase ,Choline Deficiency ,Fatty Liver ,Mice, Inbred C57BL ,Gene Expression Regulation ,Liver ,Immunology ,Disease Progression ,Intercellular Signaling Peptides and Proteins ,Inflammation Mediators ,medicine.symptom ,Steatohepatitis ,Hepatic fibrosis - Abstract
The Gas6/Axl pathway has been increasingly implicated in regeneration and tissue repair and, recently, in the control of innate immunity. In liver, we have demonstrated that Gas6 and its receptor Axl are expressed in macrophages, progenitor cells, and myofibroblasts and that Gas6 deficiency reduced inflammation and myofibroblast activation, causing delayed liver repair in response to acute injury. All these data suggest a role of Gas6/Axl signaling in pathogenesis of chronic liver diseases. In the present study, we address the role of Gas6 in steatohepatitis and progression to liver fibrosis using Gas6-deficient mice fed a choline-deficient ethionine-supplemented diet (CDE) or receiving a chronic carbon tetrachloride (CCl4) treatment. Gas6 deficiency attenuated hepatic steatosis by limiting CDE-induced downregulation of genes involved in β-oxidation observed in wild-type animals. Moreover, Gas6-deficient mice displayed reduction of hepatic inflammation, revealed by limited F4/80-positive macrophage infiltration, decreased expression of IL-1β, TNF-α, lymphotoxin-β, and monocyte chemotactic protein-1, and attenuated hepatic progenitor cell response to CDE diet. Gas6 deficiency reduced CDE-induced fibrogenesis and hepatic myofibroblast activation and decreased expression of TGF-β and collagen 1 mRNAs. After chronic CCl4injury, Gas6-deficient mice also exhibited reduced liver fibrosis as a consequence of defective macrophage recruitment compared with wild-type animals. We conclude that improvement of steatohepatitis and fibrosis in Gas6−/−mice is linked to an inhibition of the inflammatory response that controls lipid metabolism and myofibroblast activation. This study highlights the deleterious effect of Gas6 in the progression of steatosis to steatohepatitis and fibrosis.
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- 2011
13. Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice
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Fouad Lafdil, Marie-Noële Chobert, Vanessa Deveaux, P. Mavier, Toru Nakano, Y. Laperche, Elie-Serge Zafrani, Arthur Brouillet, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Shionogi Research Laboratories, Shionogi & Co, This work was supported by INSERM, University Paris 12 and Agence Nationale pour la Recherche (ANR-06-Physio-022-2)., and ANR-06-PHYS-0022,LIFR-PP,IMMUNITE INNEE ET FIBROGENESE HEPATIQUES : LE PARADIGME PORTAL(2006)
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Male ,Chemokine ,medicine.medical_treatment ,Mice ,0302 clinical medicine ,Kupffer cells ,Carbon Tetrachloride ,Oncogene Proteins ,0303 health sciences ,biology ,Kupffer cell ,Liver regeneration ,3. Good health ,medicine.anatomical_structure ,Cytokine ,Liver ,030220 oncology & carcinogenesis ,Acute Disease ,Cytokines ,Intercellular Signaling Peptides and Proteins ,Chemical and Drug Induced Liver Injury ,medicine.symptom ,Signal Transduction ,Liver repair ,Toxic hepatitis ,CD14 ,Necrosis ,03 medical and health sciences ,Axl ,Proto-Oncogene Proteins ,Hepatic Stellate Cells ,Growth arrest-specific protein 6 ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Cell Proliferation ,030304 developmental biology ,Inflammation ,Hepatology ,Suppressor of cytokine signaling 1 ,Receptor Protein-Tyrosine Kinases ,Axl Receptor Tyrosine Kinase ,Liver Regeneration ,Mice, Inbred C57BL ,Immunology ,Hepatocytes ,biology.protein ,Hepatic stellate cell ,Cancer research - Abstract
International audience; BACKGROUND/AIMS: Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury. METHODS: Toxic hepatitis was induced by a single carbon tetrachloride injection in Gas6 deficient (Gas6(-/-)) mice and liver recovery was compared with wild-type animals. RESULTS: Gas6 deficiency did not cause any change in CCl(4)-induced liver damage. At 72 h, an efficient tissue repair was observed in wild-type animals whereas in Gas6(-/-) mice, we noticed a defective wound healing accounted by reduced Kupffer cell activation revealed by a decrease in the induction of CD14, TNF-alpha, IL6 and MCP-1. Gas6-deficiency, by limiting cytokine/chemokine release, prevents hepatocyte proliferation, recruitment of circulating monocytes and accumulation of myofibroblasts in healing areas. We also report a direct chemotactic effect of Gas6 on circulating monocytes which might explain defective macrophage infiltration in liver necrotic areas of Gas6(-/-) mice. Interestingly in Gas6(-/-) mice, we observed a high and constitutive expression of Axl and an induction of the suppressor of cytokine signaling SOCS1 after CCl(4) treatment. CONCLUSIONS: The lower level of cytokines/chemokines in Gas6(-/-) mice after CCl(4) injury, is the consequence of an inhibitory signal arising from Axl receptor overexpression, leading to delayed liver repair in deficient mice.
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- 2009
14. Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts?
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Elie-Serge Zafrani, Irene Oi-Lin Ng, Y. Hayashi, A. C. Paterson, Linda D. Ferrell, Bruno Falissard, Francesco Callea, G. Malouf, Zachary Goodman, Jean François Emile, Daniel Azoulay, Hey-Chi Hsu, Michel Reynes, Masamichi Kojiro, and Stefan G. Hubscher
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Carcinoma, Hepatocellular ,Adolescent ,Medical Oncology ,Antibodies ,Pathology and Forensic Medicine ,Cholangiocarcinoma ,Diagnosis, Differential ,Young Adult ,Stroma ,Biomarkers, Tumor ,medicine ,Carcinoma ,Cluster Analysis ,Humans ,Child ,Aged ,Keratin-19 ,business.industry ,Keratin-7 ,Liver Neoplasms ,Reproducibility of Results ,Cancer ,Anatomical pathology ,Histology ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Carcinoembryonic Antigen ,Fibrolamellar hepatocellular carcinoma ,Hepatocellular carcinoma ,Hepatocytes ,Keratins ,Female ,business - Abstract
In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis.A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review.The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p0.001).The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.
- Published
- 2009
15. Primary lymphoma of the liver
- Author
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Philippe Gaulard and Elie Serge Zafrani
- Subjects
Pathology ,medicine.medical_specialty ,Liver tumor ,Lymphoma ,Hepatology ,business.industry ,Liver Neoplasms ,Liver failure ,Prognosis ,medicine.disease ,Liver Lymphoma ,Primary lymphoma ,medicine ,Humans ,business ,Liver Failure - Published
- 2008
16. Primary Hepatic Lymphoma of Mucosa-Associated Lymphoid Tissue Type: A Case Report With Cytogenetic Study
- Author
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Jean-Charles Delchier, Karen Leroy, Elie-Serge Zafrani, Marie-Helene Delfau, Jérôme Loriau, Judith Dierlamm, Eva Maria Murga Penas, Christiane Copie-Bergman, Philippe Gaulard, Marie-Therese Chaumette-Planckaert, and Wafa Koubaa Mahjoub
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Gene Rearrangement, B-Lymphocyte, Heavy Chain ,Trisomy ,Biology ,Disease-Free Survival ,Pathology and Forensic Medicine ,Liver disease ,medicine ,Humans ,Liver neoplasm ,Helicobacter ,In Situ Hybridization, Fluorescence ,Liver Neoplasms ,Lymphoma, B-Cell, Marginal Zone ,Gene rearrangement ,Middle Aged ,medicine.disease ,biology.organism_classification ,Lymphoma ,Lymphatic system ,Surgery ,Chromosomes, Human, Pair 3 ,Anatomy ,Chromosomes, Human, Pair 18 ,Mucosa-associated lymphoid tissue - Abstract
Primary hepatic lymphoma of mucosa-associated lymphoid tissue type is extremely rare. Only 38 cases have been reported to date. A case of a 59-year-old man with Helicobacter pylori—resistant gastric ulcers and Buerger disease who was followed up since 1999 is reported. A 2-cm hepatic nodule was incidentally found during partial gastrectomy and corresponded to mucosa-associated lymphoid tissue—type lymphoma without underlying liver disease. Molecular studies showed a clonal immunoglobulin heavy-chain gene rearrangement. Investigations for the mucosa-associated lymphoid tissue lymphoma-associated translocations t(11;18) and t(14;18), as well as the t(3;14)(q27;q32), were negative, whereas trisomy 3 and trisomy 18 were detected.
- Published
- 2008
17. Daily Cannabis Use: A Novel Risk Factor of Steatosis Severity in Patients With Chronic Hepatitis C
- Author
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Jean–Michel Pawlostky, Ariane Mallat, Charlotte Costentin, Christophe Hézode, Elie Serge Zafrani, Fatiha Medkour, Francoise Roudot Thoraval, Ali Hessami, Magali Bouvier–Alias, and Sophie Lotersztajn
- Subjects
Adult ,Male ,medicine.medical_specialty ,Genotype ,medicine.medical_treatment ,Marijuana Smoking ,Hepacivirus ,Severity of Illness Index ,Gastroenterology ,Body Mass Index ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Severity of illness ,medicine ,Humans ,Risk factor ,Cannabis smoking ,Hepatology ,biology ,business.industry ,Hepatitis C ,Odds ratio ,Hepatitis C, Chronic ,Middle Aged ,Viral Load ,medicine.disease ,biology.organism_classification ,Surgery ,Fatty Liver ,Logistic Models ,Liver ,Multivariate Analysis ,RNA, Viral ,Female ,Cannabis ,Steatosis ,business ,Body mass index - Abstract
Steatosis is highly prevalent in patients with chronic hepatitis C (CHC) and has been reported to increase fibrosis and reduce the rate of viral eradication. Two recent studies indicate that endocannabinoids promote experimental steatosis via activation of hepatic CB1 receptors. We therefore investigated the impact of cannabis smoking on steatosis severity during CHC.A total of 315 consecutive patients with untreated CHC undergoing liver biopsy were included. Detailed histories of recent cannabis, alcohol, and tobacco use were recorded. Steatosis, activity, and fibrosis stage were assessed by 2 pathologists according to METAVIR. Marked steatosis was defined as/=30%. Patients were categorized as cannabis nonusers (63.5%), occasional cannabis smokers (12.4%), or daily cannabis smokers (24.1%).Multivariate analysis identified 6 predictors of marked steatosis: daily cannabis use (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.01-4.5]), activity grade/=A2 (OR, 2.1; 95% CI, 1.0-4.3), genotype 3 (OR, 5.4; 95% CI, 2.6-11.3), hyperglycemia or diabetes (OR, 5.1; 95% CI, 1.8-15.0), body mass index27 kg/m(2) (OR, 2.1; 95% CI, 1.0-4.3), and serum HCV RNA load (OR, 1.7; 95% CI, 1.0-2.9). Upon adjustment of HCV genotype (3 vs non-3) or alcohol intake (30 g/day vs/=30 g/day), marked steatosis was more frequent in daily cannabis users compared with occasional users and nonusers (P = .03 and P = .008, respectively).Our results identify daily cannabis smoking as a novel independent predictor of steatosis severity during CHC and strongly argue for a steatogenic role of the cannabinoid system. Cannabis use should be discouraged in patients with CHC.
- Published
- 2008
18. Massive Blastic Infiltration of the Liver: A Cause of Fulminant Hepatic Failure
- Author
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Bernard Leclercq, Guy Chomette, Daniel Dhumeaux, Yvon Pinaudeau, Elie Serge Zafrani, and Jean-Paul Vernant
- Subjects
Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Autopsy ,Hepatic Complication ,Fulminant hepatic failure ,medicine ,Humans ,Chemotherapy ,Acute leukemia ,Hepatology ,business.industry ,Liver Diseases ,Lymphoma, Non-Hodgkin ,Liver Neoplasms ,medicine.disease ,Burkitt Lymphoma ,Lymphoma ,Liver ,Leukemia, Myeloid ,Leukemia, Monocytic, Acute ,Hyperlactatemia ,business ,Infiltration (medical) ,Hepatomegaly - Abstract
The clinical and pathological findings in four cases of fulminant hepatic failure due to massive infiltration of the liver by acute leukemia or lymphoma are reported. Liver abnormalities were found simultaneously with or led to the discovery of hematologic malignancies, and consisted of marked hepatomegaly and severe hepatocellular insufficiency associated with hyperlactatemia. The blood malignancies were peculiar in their fast cellular growth and large tumor mass. Evolution was rapidly fatal in all these cases. In another patient, marked hepatomegaly and hyperlactatemia revealed the presence of a widespread lymphoma before the appearance of hepatocellular insufficiency. Immediate chemotherapy was instituted, and complete remission without hepatic complication was obtained. It is suggested that malignant hematological diseases with fast cellular growth may present as fulminant hepatic failure. In order to avoid a rapidly fatal outcome secondary to liver failure and metabolic disorders, early recognition of these malignancies is necessary so as to assure prompt administration of appropriate chemotherapy.
- Published
- 2007
19. Differentiation of focal nodular hyperplasia from hepatocellular adenoma: Role of the quantitative analysis of gadobenate dimeglumine-enhanced hepatobiliary phase MRI
- Author
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Marion, Roux, Frederic, Pigneur, Julien, Calderaro, Laurence, Baranes, Mélanie, Chiaradia, Lambros, Tselikas, Thomas, Decaens, Charlotte, Costentin, Alexis, Laurent, Daniel, Azoulay, Ariane, Mallat, Elie-Serge, Zafrani, Alain, Rahmouni, and Alain, Luciani
- Subjects
Adult ,Male ,Liver Neoplasms ,Contrast Media ,Middle Aged ,Image Enhancement ,Magnetic Resonance Imaging ,Sensitivity and Specificity ,Adenoma, Liver Cell ,Diagnosis, Differential ,Young Adult ,Meglumine ,Liver ,ROC Curve ,Focal Nodular Hyperplasia ,Organometallic Compounds ,Humans ,Female ,Aged ,Retrospective Studies - Abstract
To determine the value of quantitative analysis of the hepatobiliary phase (HBP) in gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) to differentiate focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA).Thirty-eight patients bearing 67 lesions (40 FNH; 27 HCA) were retrospectively included in this Institutional Review Board-approved study. The same volumetric interpolated breath-hold examination (VIBE) T1 -weighted sequences were performed before and after contrast injection on a 1.5T MRI, with HBP images acquired with a mean delay of 80 minutes (range 60-120 min). After a visual assessment of lesions enhancement (qualitative HBP analysis), the HBP signal intensity ratio (SIR) and the lesion-to-liver contrast enhancement ratio (LLCER) were calculated for each lesion by two observers (Mann-Whitney test). The sensitivities, specificities (receiver operating characteristic [ROC] curve analysis) and interobserver correlation (intraclass coefficient, ICC) of quantitative HBP analysis were determined.All FNH and 44.4% of HCA appeared hyper- or isointense relative to the adjacent liver on qualitative HBP analysis. The mean SIR (P 0.01) and LLCER (P 0.0001) of FNH were significantly higher than that of HCA. The area under the ROC curve for the differentiation of FNH from HCA with LLCER was 0.98 for both observers. With a cutoff value of -0.3%-observer 1 with highest experience- LLCER assessment provided respective sensitivity and specificity values of 100% and 96.2% for the differentiation of FNH from HCA. The ICC was 0.7 for SIR measurements and 0.8 for LLCER measurements.Quantitative LLCER assessment allows an accurate differentiation of FNH from HCA, even in hyper- or isointense HCA on HBP images.
- Published
- 2015
20. Primary biliary cirrhosis: proposal for a new simple histological scoring system
- Author
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Dominique Wendum, Christophe Corpechot, Pierre Bedossa, Pierre-Yves Boëlle, Marie-Christine Saint-Paul, Sophie Michalak, Frédéric Charlotte, Elie-Serge Zafrani, Olivier Chazouillères, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)
- Subjects
Liver Cirrhosis ,medicine.medical_specialty ,Scoring system ,Cirrhosis ,Organ Dysfunction Scores ,Biopsy ,[SDV]Life Sciences [q-bio] ,Interface hepatitis ,Gastroenterology ,Hepatitis ,Ductopenia ,Primary biliary cirrhosis ,Fibrosis ,Internal medicine ,Medicine ,Humans ,Observer Variation ,Hepatology ,medicine.diagnostic_test ,business.industry ,Bile duct ,Liver Cirrhosis, Biliary ,Reproducibility of Results ,medicine.disease ,Prognosis ,3. Good health ,medicine.anatomical_structure ,Liver biopsy ,business ,Nuclear medicine - Abstract
International audience; Background & AimsA simple and reproducible evaluation of non diagnostic histological lesions related to prognosis remains crucial in primary biliary cirrhosis (PBC). Presently there is no satisfactory simple scoring system analysing them reliably. We elaborated a semi-quantitative scoring system that assesses fibrosis, lymphocytic interface hepatitis (LIH) and ductopenia, separately. This study was aimed to evaluate its intra/interobserver reproducibility and its correlation with the main biochemical data.MethodsLiver biopsies from 33 consecutive newly diagnosed PBC patients were independently analysed by five liver pathologists. Fibrosis was classified into five stages (portal/periportal fibrosis/few septa/numerous septa/cirrhosis) and LIH into four grades. The bile duct ratio (BDR), i.e. ratio of the number of portal tracts with ducts to total number of portal tracts, Ludwig's and Scheuer's stages were evaluated. Intra and interobserver agreements were assessed. Histological results were correlated to the biochemical data.ResultsMost patients had an early disease on clinical and biological parameters. The biopsies measured 23mm on average (range 12 – 40mm). Intraobserver reproducibility was substantial for fibrosis (κ=0.68), LIH (κ=0.69) and BDR (ICC=0.69). Interobserver agreement for fibrosis was fair with the 5-class system (κ=0.36), moderate with a 4-class system (κ=0.56). moderate for LIH (κ=0.59) and BDR (ICC=0.50). Ludwig's and Scheuer's staging showed a fair interobserver agreement (κ=0.32, κ=0.31 respectively). Our system showed better correlations with biochemistry than Ludwig's and Scheuer's systems did.ConclusionsThis simple scoring system, assessing fibrosis, LIH and BDR separately, has a substantial intraobserver and a moderate interobserver reproducibility. Its prognostic relevance has to be evaluated.
- Published
- 2015
21. Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections
- Author
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Daniel Dhumeaux, Christophe Hézode, Elie-Serge Zafrani, Françoise Roudot-Thoraval, and Jean-Michel Pawlotsky
- Subjects
Adult ,Male ,medicine.medical_specialty ,Genotype ,Hepatitis C virus ,Hepacivirus ,medicine.disease_cause ,Gastroenterology ,Lesion ,Viral Proteins ,In vivo ,Fibrosis ,Virology ,Internal medicine ,Humans ,Medicine ,Hepatology ,business.industry ,virus diseases ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,digestive system diseases ,Fatty Liver ,Infectious Diseases ,Female ,medicine.symptom ,Steatosis ,business ,Viral load ,Body mass index - Abstract
Summary. This study reports evidence that hepatocellular steatosis, a frequent histological feature of chronic hepatitis C, is principally metabolic in hepatitis C virus (HCV) genotype 1-infected patients, whereas it is principally virus-induced in HCV genotype 3-infected patients. Multivariate analysis of data on 176 patients with chronic hepatitis C revealed that the severity of steatosis was independently related to HCV RNA load alone in patients infected by HCV genotype 3, whereas it was independently related to the body mass index, daily alcohol intake and histological activity grade (but not viral load) in patients infected by HCV genotype 1. These findings suggest that steatosis is a cytopathic lesion induced by HCV genotype 3, whereas HCV genotype 1 is not steatogenic per se or at the usual in vivo expression levels.
- Published
- 2004
22. Profiles of the 2 INK4a gene products, p16 and p14ARF, in human reference urothelium and bladder carcinomas, according to pRb and p53 protein status*1
- Author
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Ahmad Daher, Dominique K. Chopin, Clément Claude Abbou, Marie-Aude Le Frère-Belda, Sixtina Gil Diez de Medina, Elie Serge Zafrani, Didier Heudes, Nadine Martin, Benoit Albaud, Jean Paul Thiery, and François Radvanyi
- Subjects
Tumor suppressor gene ,Retinoblastoma protein ,Biology ,medicine.disease_cause ,Molecular biology ,Pathology and Forensic Medicine ,Gene product ,p14arf ,Cyclin-dependent kinase ,biology.protein ,medicine ,Cancer research ,Gene silencing ,Urothelium ,Carcinogenesis - Abstract
The INK4a/ARF locus encodes 2 cell cycle regulatory proteins: p16 and p14 ARF . P16 inhibits the activities of cdks, which maintain the retinoblastoma protein (pRb) in its active hypophosphorylated state. P14 ARF blocks MDM2-induced p53 degradation and transactivational silencing. In this study, we investigated the expression of p16 and p14 ARF in reference human urothelium and in 51 urothelial carcinomas (UCs) of all stages and grades, by reverse transcription-polymerase chain reaction (RT-PCR). Patterns of p14 ARF and p16 expression were compared with each other and then with patterns of p53 and pRb protein expression, respectively, as determined by immunohistochemistry. P14 ARF and p16 mRNAs were present at low levels or were undetectable in reference urothelia and in most superficial tumors, whereas they were present at high levels in a subset of tumors of advanced stage and high grade. The expression profiles of these 2 mRNAs were correlated in all but 4 cases, indicating that the 2 INK4a products may have nonredundant functions. Forty-six of the 51 tumors (90%) presented changes to or a lack of activation of the p14 ARF -p53 pathway and were p53 positive (n = 10), p14 ARF negative (n = 23), or both p53 positive and p14 ARF negative (n = 13), suggesting that these 2 components of the pathway may be altered or nonactivated. Markedly high levels of p16 mRNA (n = 5) were associated with the absence of pRb expression, with the exception of 1 case in which the p16 gene contained a deletion mutation. A lack of p16 mRNA or low levels of this mRNA were associated with pRb detection in all but 1 case. In invasive UCs, the p16-pRb pathway, the p14 ARF -p53 pathway, or in many cases both pathways were altered or not activated, demonstrating the involvement of these pathways in invasive bladder tumorigenesis.
- Published
- 2004
23. Pretreatment p53 Nuclear Overexpression as a Prognostic Marker in Superficial Bladder Cancer Treated with Bacillus Calmette–Guérin (BCG)
- Author
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R. Quitela, Clément-Claude Abbou, Fabien Saint, Elie Serge Zafrani, J. Bellot, A. Hoznek, S. Gil Diez De Medina, D. Chopin, M.A. Le Frere Belda, Zivko Popov, and J.J. Patard
- Subjects
Adult ,Male ,Oncology ,Nephrology ,medicine.medical_specialty ,Pathology ,Tumor suppressor gene ,Urology ,Urinary system ,Disease-Free Survival ,Adjuvants, Immunologic ,Internal medicine ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Cell Nucleus ,Bacillus (shape) ,Carcinoma, Transitional Cell ,Urinary bladder ,Bladder cancer ,biology ,business.industry ,Carcinoma in situ ,Middle Aged ,Prognosis ,biology.organism_classification ,medicine.disease ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Urinary Bladder Neoplasms ,BCG Vaccine ,Disease Progression ,Superficial bladder cancer ,biology.protein ,Cancer research ,Female ,Neoplasm Recurrence, Local ,Tumor Suppressor Protein p53 ,Antibody ,business ,Immunostaining - Abstract
Introduction: Altered p53 gene product correlates with the stage and grade of bladder tumor, but its value as a predictor of BCG response has been disappointing. In order to revisite the prognostic value of pretreatment p53 nuclear overexpression for the BCG response, we studied a large cohort of consecutive patients with superficial bladder cancer treated with BCG. Methods: From 1988 to 2001, 102 patients with a history of multifocal, recurrent, and/or high-risk papillary transitional cell carcinoma or carcinoma in situ, were treated for the first time with BCG. p53 immunostaining was performed on paraffin-embedded tissues using monoclonal antibody DO7 and an automated immunostainer. Special attention was paid to the conditions of tumor fixation. p53 overexpression was defined as more than 20% tumor cells with p53-stained nuclei. Results: Immunostaining was significantly higher for Ta/T1 G3 ± Cis (p
- Published
- 2004
24. Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis
- Author
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Elie-Serge Zafrani, Laurent Castera, Christophe Hézode, Françoise Roudot-Thoraval, Jean-Michel Pawlotsky, Daniel Dhumeaux, and I. Lonjon
- Subjects
Adult ,Male ,medicine.medical_specialty ,Genotype ,Biopsy ,Hepacivirus ,Hepatitis C virus ,medicine.disease_cause ,Antiviral Agents ,Gastroenterology ,Internal medicine ,medicine ,Humans ,Cytopathic effect ,biology ,business.industry ,Fatty liver ,Hepatitis C ,Odds ratio ,Hepatitis C, Chronic ,Middle Aged ,biology.organism_classification ,medicine.disease ,Fatty Liver ,Treatment Outcome ,Liver ,Multivariate Analysis ,Immunology ,Disease Progression ,Female ,Steatosis ,business - Abstract
Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies.A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI)28 kg/m(2); absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies.Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non-responders (NR) (64% v 31%; p0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (19% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61-22.9); p = 0.01), severe steatosis (OR 5.50 (95% CI 1.54-19.6); p = 0.01), HCV genotype 3 (OR 2.90 (95% CI 0.85-10.0); p = 0.07), and BMI25 kg/m(2) (OR 0.24 (95% CI 0.08-0.73); p = 0.02).Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis.
- Published
- 2004
25. Non-alcoholic fatty liver disease: an emerging pathological spectrum
- Author
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Elie Serge Zafrani
- Subjects
Liver Cirrhosis ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Cirrhosis ,Mitochondria, Liver ,Disease ,Gastroenterology ,Pathology and Forensic Medicine ,Liver disease ,Insulin resistance ,Fibrosis ,Internal medicine ,Diabetes mellitus ,Humans ,Medicine ,Obesity ,Molecular Biology ,business.industry ,Liver Neoplasms ,Fatty liver ,Cell Biology ,General Medicine ,medicine.disease ,Hepatitis C ,Fatty Liver ,Oxidative Stress ,Diabetes Mellitus, Type 2 ,Cytokines ,Insulin Resistance ,Steatohepatitis ,business - Abstract
The spectrum of pathological lesions observed in non-alcoholic fatty liver disease (NAFLD) is wide and strongly resembles that of alcohol-induced liver disease. It ranges from fatty liver to steatohepatitis, progressive fibrosis and cirrhosis. Hepatocellular carcinoma is a possible complication of NAFLD, but whether it is related to frequently associated metabolic disorders (e.g., overweight, diabetes) or to underlying cirrhosis is unclear. This disease is the result of a multi-factorial process in which insulin resistance seems to play a major role in the initial accumulation of fat in the liver, whereas multiple causes of mitochondrial dysfunction and oxidative stress can induce the secondary occurrence of necroinflammatory lesions and fibrosis. Genetic factors might explain why only some patients with simple steatosis will develop steatohepatitis and fibrosis. Due to the increasing prevalence of obesity in Western countries, NAFLD will possibly be a public health problem and the liver disease of the future.
- Published
- 2004
26. Hepatosplenic T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients
- Author
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Felix Reyes, Jean-Pierre Farcet, Elie-Serge Zafrani, Eric Labouyrie, Beatrice Delmas-Marsalet, Hervé Tilly, Jean-François Emile, Bertrand Arnulf, Philippe Gaulard, Eric Deconinck, Christian Bastard, Frédéric Charlotte, Pierre Lederlin, Véronique Leblond, Régis Angonin, and Karim Belhadj
- Subjects
Adult ,Male ,Herpesvirus 4, Human ,medicine.medical_specialty ,Pathology ,Adolescent ,Hepatosplenic T-cell lymphoma ,medicine.medical_treatment ,Immunology ,Splenectomy ,Lymphoma, T-Cell ,Biochemistry ,Immunophenotyping ,Immunocompromised Host ,Postoperative Complications ,Bone Marrow ,Cell Movement ,T-Lymphocyte Subsets ,Internal medicine ,medicine ,Humans ,T-cell lymphoma ,Treatment Failure ,Retrospective Studies ,Chromosome Aberrations ,Hematology ,business.industry ,Receptors, Antigen, T-Cell, gamma-delta ,Cell Biology ,Middle Aged ,Prognosis ,medicine.disease ,Kidney Transplantation ,Thrombocytopenia ,Malaria ,Lymphoma ,medicine.anatomical_structure ,Splenomegaly ,Neoplastic Stem Cells ,Female ,Bone marrow ,CD5 ,business ,Chromosomes, Human, Pair 7 ,Hepatomegaly - Abstract
We report on the characteristics of 21 patients with hepatosplenic gammadelta T-cell lymphoma (HSgammadeltaTCL), an entity recognized since 1994 in the Revised European American Lymphoma (REAL) classification. Median age was 34 years. Patients had splenomegaly (n = 21), hepatomegaly (n = 15), and thrombocytopenia (n = 20). Histopathologic findings were homogeneous and showed the presence of medium-sized lymphoma cells within the sinusoids of splenic red pulp, liver, and bone marrow. Marrow involvement was usually mild but could be demonstrated by phenotyping in all patients. Cells were CD3+CD5-, expressed the gammadelta T-cell receptor, and had a nonactivated cytotoxic cell phenotype (TIA-1+, granzyme B-). Most patients were CD4-/CD8- (16 of 18); CD56+ (15 of 18), expressed the Vdelta1epitope (Vd1+/Vd2-/Vd3-) (9 of 12); and were negative for Epstein-Barr virus (EBV) (18 of 20). Isochromosome arm 7q was documented in 9 of 13 patients. Eight patients had previously undergone kidney transplantation or had a history of systemic lupus, Hodgkin disease, or malaria. Prognosis was poor; median survival time was 16 months, and all but 2 patients ultimately died despite consolidative or salvage high-dose therapy. In conclusion, HSgammadeltaTCL is a disease with distinctive clinical, histopathologic, and phenotypic characteristics. Bone marrow biopsy with combined phenotyping is sufficient for diagnosis, and splenectomy is therefore unwarranted. Current treatment modalities appear to be ineffective in most patients.
- Published
- 2003
27. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study
- Author
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Elie-Serge Zafrani, Françoise Roudot-Thoraval, Daniel Dhumeaux, Christophe Hézode, I. Lonjon, and Jean-Michel Pawlotsky
- Subjects
medicine.medical_specialty ,Cirrhosis ,Hepatology ,business.industry ,Gastroenterology ,Alcohol ,Hepatitis C ,medicine.disease ,Surgery ,chemistry.chemical_compound ,chemistry ,Fibrosis ,Internal medicine ,medicine ,Pharmacology (medical) ,Steatosis ,Risk factor ,Prospective cohort study ,business ,Complication - Abstract
Summary Aim : To evaluate the effects of minimal to moderate alcohol consumption on the severity of histological lesions in patients with chronic hepatitis C. Methods : Daily alcohol intake (none, 1–20, 21–30, 31–50 g/day) and histological activity and fibrosis were recorded in 260 patients with chronic hepatitis C. Results : The proportion of patients with moderate (A2) or marked (A3) activity increased gradually from 53.8% in abstinent patients to 86.5% for an intake between 31 and 50 g/day (P = 0.003). In multivariate analysis, age > 40 years, alcohol intake between 31 and 50 g/day and moderate or severe steatosis were independently related to histological activity. The proportion of patients with moderate (F2) or marked (F3) fibrosis or cirrhosis (F4) gradually increased from 29.0% in abstinent patients to 67.6% for an intake between 31 and 50 g/day (P
- Published
- 2003
28. Prolonged cholestasis and ductopenia following gold salt therapy
- Author
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Céline Basset, Jacqueline Vadrot, Jacques Denis, Joël Poupon, and Elie Serge Zafrani
- Subjects
Pathology ,medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Sialadenitis ,Interlobular bile ducts ,Ductopenia ,Cholestasis ,Liver biopsy ,Sicca syndrome ,Gold salts ,medicine ,Eosinophilia ,medicine.symptom ,business ,medicine.drug - Abstract
Hepatotoxicity, predominantly cholestatic, is a rare adverse effect of gold salt therapy, which usually completely resolves within a few months. We report the case of a female patient treated for rheumatoid arthritis, who had gold salt overdose, and in whom acute cholestatic hepatitis occurred three weeks after beginning of therapy. Evolution of gold concentration was followed in plasma and urine, as well as in cutaneous and liver dry tissue. Liver biopsy showed marked inflammatory changes of interlobular bile ducts that evolved towards ductopenia, which was responsible for prolonged cholestasis still present 15 months later. In addition, sialadenitis with sicca syndrome was noted six months after onset of the disease. The mechanism of hepatotoxicity was probably immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia. This is the first report of gold salt hepatotoxicity with histological demonstration of cholangitis followed by ductopenia.
- Published
- 2003
29. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis
- Author
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Jean-Charles Nault, Elie Serge Zafrani, Jessica Zucman-Rossi, Massimo Roncalli, Julien Calderaro, Luca Di Tommaso, Charles Balabaud, and Paulette Bioulac-Sage
- Subjects
Liver Cirrhosis ,Male ,Pathology ,medicine.medical_specialty ,Cirrhosis ,Carcinoma, Hepatocellular ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Glypican 3 ,Internal medicine ,medicine ,Carcinoma ,Biomarkers, Tumor ,Humans ,Telomerase reverse transcriptase ,Promoter Regions, Genetic ,Telomerase ,Aged ,Mutation ,Hepatology ,Liver Neoplasms ,Middle Aged ,medicine.disease ,Cell Transformation, Neoplastic ,Hepatocellular carcinoma ,Cancer research ,Female ,Carcinogenesis ,Precancerous Conditions - Abstract
Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC. Conclusion: Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC. (Hepatology 2014;60:1982–1991)
- Published
- 2014
30. p15INK4b in bladder carcinomas: decreased expression in superficial tumours
- Author
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Ahmad Daher, Florence Besse, Elie Serge Zafrani, S Gil-Diez-de-Medina, David Cappellen, Clément-Claude Abbou, M A Le Frère-Belda, François Radvanyi, D. Chopin, and J.P. Thiery
- Subjects
Cancer Research ,Tumor suppressor gene ,Transcription, Genetic ,Urinary Bladder ,Down-Regulation ,Cell Cycle Proteins ,Biology ,medicine.disease_cause ,urologic and male genital diseases ,human transitional cell carcinoma ,p15 ,Organ Culture Techniques ,Gene expression ,medicine ,Tumor Cells, Cultured ,Humans ,Neoplastic transformation ,Neoplasm Invasiveness ,RNA, Messenger ,RNA, Neoplasm ,Urothelium ,bladder ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase Inhibitor p15 ,Carcinoma, Transitional Cell ,Urinary bladder ,Genes, p16 ,Tumor Suppressor Proteins ,Homozygote ,cyclin-dependent kinase inhibitor ,Regular Article ,DNA Methylation ,medicine.disease ,female genital diseases and pregnancy complications ,medicine.anatomical_structure ,Transitional cell carcinoma ,Oncology ,Urinary Bladder Neoplasms ,Chromosomal region ,Cancer research ,CpG Islands ,Carcinogenesis ,Gene Deletion - Abstract
The p15 gene which encodes a cyclin-dependent kinase inhibitor, is located in the 9p21 chromosomal region that is frequently deleted in human bladder transitional cell carcinomas (TCCs). The aim of the present paper is to study the potential involvement of the p15 gene in the evolution of TCCs. p15 mRNA expression was investigated by semi-quantitative RT-PCR in a series of 75 TCCs, 13 bladder cell lines and 6 normal bladder urothelia by semi-quantitative RT-PCR. p15 was expressed in the normal urothelium but p15 mRNA levels were significantly decreased in 66% of the superficial (Ta-T1) TCCs (P = 0.0015). In contrast, in muscle-invasive (T2-T4) TCCs, p15 expression differed widely between samples. p16 mRNA levels were also studied and there was no correlation between p15 and p16 mRNA levels, thus indicating that the two genes were regulated independently. Lower p15 expression in superficial tumours did not reflect a switch from quiescence to proliferative activity as normal proliferative urothelial controls did not present decreased p15 mRNA levels relative to quiescent normal urothelia. We further investigated the mechanisms underlying p15 down regulation. Homozygous deletions of the p15 gene, also involving the contiguous p16 gene, were observed in 42% of the TCCs with decreased p15 expression. No hypermethylation at multiple methylation-sensitive restriction sites in the 5′-CpG island of p15 was encountered in the remaining tumours. Our data suggest that decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium and that a mechanism other than homozygous deletions or hypermethylation, may be involved in p15 down regulation. © 2001 Cancer Research Campaign http://www.bjcancer.com
- Published
- 2001
31. Declining Autopsy Rate in a French Hospital
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François Lemaire, Patrick Chariot, Vivien Pautot, Raphaël Porcher, Karine Witt, Guy Thomas, and Elie Serge Zafrani
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Pediatrics ,medicine.medical_specialty ,business.industry ,Autopsy ,General Medicine ,Bioethics ,Medical care ,Pathology and Forensic Medicine ,Medical Laboratory Technology ,Family medicine ,medicine ,Autopsy report ,In patient ,University teaching ,business - Abstract
Context.—Autopsy rates have been declining throughout the world, although preservation of the autopsy is considered a fundamental principle of medical care. In France, the 1994 bioethics law requires physicians to inform relatives before performing an autopsy. Objective.—To analyze the following factors that potentially influence hospital autopsy rates: legal constraints, autopsy reporting times, opinions of physicians requesting autopsies and pathologists regarding the usefulness of autopsy in patient care, and use of autopsy material in research publications. Design.—Record of the annual numbers of deaths and autopsies during a 10-year period (1988–1997). Record of the delays for transmission of final autopsy report to the requesting physician. Questionnaire analyzing the possible factors influencing autopsy rate. Categorization of articles published by pathologists according to the use of autopsy material. Setting.—A 1000-bed, university teaching hospital in the Paris, France, area. Participants.—Questionnaire addressed to physicians, head nurses, and mortuary staff. Results.—A total of 1454 autopsies were reviewed. The autopsy rate declined from 15.4% in 1988 to 3.7% in 1997. This decline was marked after 1994 and tended to be slower for neurologic indications than for other indications. The final report had not been communicated within 180 days in 620 (42.6%) of 1454 autopsies. Fifty-five of 105 respondents considered that the bioethics law was one cause of the recent decrease of autopsy rate. Considering the contribution of autopsy to medical research, 94 (81%) of 116 articles dealing with central nervous system but only 28 (6%) of 464 articles dealing with other organs used autopsy-derived material. Conclusions.—The 1994 bioethics law seems to contribute to the decline of autopsy. Inadequate delays for communicating autopsy results are frequent. Except for neuropathologists, autopsy is a minor source of research material.
- Published
- 2000
32. Randomized Trial of Interferon-Alpha plus Ursodeoxycholic Acid versus Interferon plus Placebo in Patients with Chronic Hepatitis C Resistant to Interferon
- Author
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J. Guechot, Ulrich Beuers, J. P. A. Zarski, Elie-Serge Zafrani, D. Vetter, R.E. Poupon, P. E. Queneau, Y. Chretien, Lawrence Serfaty, G. Thieffin, D. Larrey, M. F. St Marc Girardin, J. D. Grange, H. Mathiex-Fortunet, Gustav Paumgartner, Renée E. Poupon, A. M. Bonnand, Christian Trepo, J.-J. Raabe, J. P. Capron, and Other departments
- Subjects
Adult ,Male ,Cholagogues and Choleretics ,medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,Alpha interferon ,Placebo ,Antiviral Agents ,Gastroenterology ,Statistics, Nonparametric ,law.invention ,Double-Blind Method ,Randomized controlled trial ,Reference Values ,law ,Interferon ,Internal medicine ,medicine ,Humans ,Aged ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Ursodeoxycholic Acid ,Interferon-alpha ,Drug Resistance, Microbial ,Hepatitis C ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,Ursodeoxycholic acid ,Treatment Outcome ,Immunology ,Drug Therapy, Combination ,Female ,Interferons ,business ,Follow-Up Studies ,medicine.drug - Abstract
Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids
- Published
- 2000
33. Nuclear Accumulation of Mutated β-Catenin in Hepatocellular Carcinoma Is Associated with Increased Cell Proliferation
- Author
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Yu Wei, Claire Angélique Renard, Marie Annick Buendia, Jeanne Tran Van Nhieu, Elie Serge Zafrani, and Daniel Cherqui
- Subjects
Adult ,Male ,Carcinoma, Hepatocellular ,Beta-catenin ,Proliferative index ,Somatic cell ,Short Communication ,DNA Mutational Analysis ,medicine.disease_cause ,Polymerase Chain Reaction ,Pathology and Forensic Medicine ,Recurrence ,Mitotic Index ,medicine ,Humans ,Amino Acid Sequence ,beta Catenin ,Aged ,Cell Nucleus ,Mutation ,biology ,Liver Neoplasms ,Wnt signaling pathway ,Middle Aged ,Immunohistochemistry ,Survival Rate ,Cytoskeletal Proteins ,Ki-67 Antigen ,Tumor progression ,Catenin ,Trans-Activators ,Cancer research ,biology.protein ,Female ,Carcinogenesis ,Cell Division - Abstract
Inappropriate activation of the Wnt pathway resulting from beta-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivo effects of mutated beta-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the beta-catenin gene, and the expression and subcellular localization of beta-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in beta-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of beta-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of beta-catenin was significantly associated with the presence of mutations in the beta-catenin gene (P0.005). Moreover, nuclear beta-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/beta-catenin pathway in HCC results mainly from somatic mutations in the beta-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.
- Published
- 1999
34. [Untitled]
- Author
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Martine Blazquez, Elie Serge Zafrani, Ariane Mallat, Bernard Campillo, Jean-Claude Bognel, and Jean-Philippe Richardet
- Subjects
Long lasting ,medicine.medical_specialty ,Amoxicillin/clavulanic acid ,Physiology ,business.industry ,Gastroenterology ,Amoxicillin ,medicine.disease ,Ductopenia ,Transplant surgery ,Cholestasis ,Internal medicine ,Clavulanic acid ,medicine ,Acide clavulanique ,business ,medicine.drug - Published
- 1999
35. Myofibroblasts and hepatocellular carcinoma: an in vivo and in vitro study
- Author
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Elie Serge Zafrani, Anne-Marie Preaux, Daniel Cherqui, Ariane Mallat, Jeanne Tran Van Nhieu, Philippe Mavier, and Isabelle Brocheriou
- Subjects
Liver Cirrhosis ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Cirrhosis ,Biology ,Immunoenzyme Techniques ,Tumor Cells, Cultured ,medicine ,Extracellular ,Humans ,Hepatology ,Cell growth ,Liver cell ,Liver Neoplasms ,Muscle, Smooth ,DNA ,Fibroblasts ,Blotting, Northern ,medicine.disease ,Actins ,Dysplasia ,Hepatocellular carcinoma ,RNA ,Immunohistochemistry ,Myofibroblast ,Cell Division - Abstract
Background/Aims: The number of perisinusoidal myofibroblasts has been shown to be increased in hepatocellular carcinoma, as compared to cirrhosis. This increase might suggest a cooperative relationship between tumour cells and myofibroblasts. To assess this relationship, we undertook: (a) a immunohistochemical study to confirm the existence of an increased number of perisinusoidal myofibroblasts in human hepatocellular carcinoma, as compared to cirrhosis with or without liver cell dysplasia, (b) an in vitro study testing the role of normal or tumoral human hepatocytes in myofibroblast proliferation. Methods: Forty explanted cirrhotic livers, including 14 with hepatocellular carcinoma and 24 with liver cell dysplasia, were studied. Myofibroblasts were detected by immunohistochemistry using an antibody directed against alpha-smooth muscle actin. Hepatic myofibroblasts in culture were obtained by outgrowth from human liver explants. Results: There was a progressive increase in the number of perisinusoidal myofibroblasts, from cirrhotic nodules without dysplasia to liver cell dysplasia and hepatocellular carcinoma. Conditioned medium from isolated normal human hepatocytes had only minor mitogenic effects on myofibroblasts, as assessed by measuring DNA synthesis and cell growth. In contrast, conditioned medium from a human hepatoma cell line (HepG2 cells) markedly stimulated the proliferation of human myofibroblasts. This mitogenic activity was stored in HepG2 cells and secreted in the extracellular medium rather than being simply released following cell lysis. Conclusion: These results suggest that the increased number of myofibroblasts in hepatocellular carcinoma might be due to a paracrine mechanism involving soluble mitogenic factor(s) secreted by tumour cells.
- Published
- 1998
36. A histopathological study of the effects of 6-month versus 12-month interferon α-2b therapy in chronic hepatitis C
- Author
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Marianne Ziol, Françoise Roudot-Thoraval, Yves Deugnier, Daniel Dhumeaux, Elie Serge Zafrani, Métreau Jm, and Jeanne Tran Van Nhieu
- Subjects
Liver Cirrhosis ,medicine.medical_specialty ,Pathology ,Biopsy ,Injections, Subcutaneous ,Hepatitis C virus ,Alpha interferon ,Interferon alpha-2 ,medicine.disease_cause ,Antiviral Agents ,Gastroenterology ,Necrosis ,Predictive Value of Tests ,Fibrosis ,Interferon ,Internal medicine ,medicine ,Humans ,Fat Necrosis ,Interferon alfa ,Hepatology ,medicine.diagnostic_test ,business.industry ,Interferon-alpha ,Alanine Transaminase ,gamma-Glutamyltransferase ,medicine.disease ,Hepatitis C ,Recombinant Proteins ,Treatment Outcome ,Liver biopsy ,Chronic Disease ,Regression Analysis ,Histopathology ,Steatosis ,business ,Biomarkers ,Cell Division ,Follow-Up Studies ,medicine.drug - Abstract
Background/Aims :Interferon therapy has been shown to have beneficial effects in chronic hepatitis C, but the optimal duration of treatment has not been clearly defined. The aims of this study were: (a) to perform a detailed histological comparison of the effects of a 6-month and a 12-month treatment using the Knodell score as well as a recently proposed grid of analysis, (b) to determine possible histological predictive factors of response to therapy, and (c) to attempt to relate histological and biochemical modifications. Methods :Liver biopsies obtained before and 18 months after beginning of treatment were therefore compared in 26 patients treated for 6 months, and in 34 patients treated for 12 months. Results :Six months of treatment induced a significant decrease in periportal ( p =0.02) and intralobular ( p =0.004) hepatocyte necrosis. The same items were improved in the 12-month-related patiens but in addition, portal inflammation ( p =0.01), bile duct lesions ( p =0.03), lymphiod aggregates ( p =0.002) and fibrosis ( p =0.008)_were also improved, according to the Knodell score. Low scores for fibrosis, steatosis and cholangiolar proliferation on the pretreatment liver biopsy could be considered predictive factors for alanine aminotransferase normalization at 6 months. There was no relationship between biochemical response and modification of fibrosis. Conclusion : Our results suggest that: (a) a decrease in fibrosis might be detected only after a 12-month interferon treatment, and (b) initial fibrosis, cholangiolar proliferation and steatosis are predictive of a lack of biochemical response. The absence of a relation between biochemical response and evolution of fibrosis implies that the evaluation of treatments in chronic hepatitis C should always include a detailed histopathological study.
- Published
- 1996
37. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis
- Author
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Raoul Poupon, Renée E. Poupon, J T Van Nhieu, Anne-Marie Bonnand, Pierre-Michel Huet, and Elie Serge Zafrani
- Subjects
medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,biology ,business.industry ,Biliary cirrhosis ,medicine.disease ,Gastroenterology ,Ursodeoxycholic acid ,Elevated alkaline phosphatase ,chemistry.chemical_compound ,Primary biliary cirrhosis ,Esophageal varices ,chemistry ,Alanine transaminase ,Liver biopsy ,Internal medicine ,medicine ,biology.protein ,Colchicine ,medicine.symptom ,business ,medicine.drug - Abstract
The efficacy of colchicine combined with ursodeoxycholic acid (UDCA) and UDCA alone in the treatment of patients with nonadvanced primary biliary cirrhosis (PBC) was evaluated in a 2-year controlled study. Seventy-four patients with PBC who had been treated previously with UDCA (at least 8 months) but still had abnormal liver test results, especially elevated alkaline phosphatase activity, were randomized to be administered colchicine (1 mg/d, 5 days per week) (n = 37) or a placebo (n = 37). In addition, the patients were treated with UDCA (13-15 mg x kg(-1) x day(-1)). The patients underwent clinical examination and liver tests every 6 months and upper endoscopy and liver biopsy at entry and at 2 years. Procollagen type III aminoterminal peptide (PIIINP), hyaluronic acid, and sulfobromophthalein (BSP) elimination kinetics were determined at entry and after 2 years. After 2 years of treatment, relative to UDCA, colchicine combined with UDCA did not significantly improve symptoms, laboratory findings (serum bilirubin level, alkaline phosphatase and alanine transaminase [ALT] activities, immunoglobulin [Ig] M level), serum markers of fibrosis, or histological features, except lobular inflammation. Colchicine did tend to slightly reduce the progression of esophageal varices; however, the difference was not significant. BSP elimination kinetics (45-minute retention percentage) was significantly improved when treated with colchicine. During the 2-year study, the only clinical complications were variceal bleeding in one patient administered colchicine and two administered the placebo. Two patients died from nonliver causes. One severe adverse effect (peripheral neuromyopathy) was observed in a colchicine-treated patient. In conclusion, this study suggests that colchicine appears to provide a slight advantage relative to UDCA alone in patients with nonadvanced PBC.
- Published
- 1996
38. Carcinome hépatocellulaire en l’absence de cirrhose au cours d’une stéato-hépatite non alcoolique
- Author
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Elie-Serge Zafrani, Rabia Bencheqroun, Alain Luciani, Christophe Duvoux, and Daniel Dhumeaux
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,Gastroenterology ,medicine ,General Medicine ,business - Abstract
Resume Tous les carcinomes hepatocellulaires jusqu’ici rapportes chez des malades atteints de steato-hepatite non alcoolique se sont developpes sur une cirrhose pre-existante. Nous rapportons ici l’observation d’un homme de 68 ans atteint d’une steato-hepatite non alcoolique et chez qui un carcinome hepatocellulaire est survenu en l’absence de cirrhose. Cette observation conduit a envisager une filiation entre la steato-hepatite non alcoolique et/ou l’obesite, et le carcinome hepatocellulaire independamment de la cirrhose et invite a la conduite d’etudes epidemiologiques pour preciser la reelle incidence de cette association.
- Published
- 2004
39. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver
- Author
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Adrien, Guillot, Nabila, Hamdaoui, Alexandra, Bizy, Keve, Zoltani, Rachid, Souktani, Elie-Serge, Zafrani, Ariane, Mallat, Sophie, Lotersztajn, and Fouad, Lafdil
- Subjects
Liver Cirrhosis ,Male ,Interleukins ,Macrophages ,Interleukin-17 ,Mice, Inbred C57BL ,Receptor, Cannabinoid, CB2 ,Mice ,STAT5 Transcription Factor ,Animals ,Th17 Cells ,Bile Ducts ,Myofibroblasts ,Ligation - Abstract
Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2(-/-) mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2(-/-) BDL mice. In vitro, differentiation of CD4(+) naïve T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17-induced proinflammatory gene expression.These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production.
- Published
- 2012
40. Definitive Diagnosis with the Use of Monoclonal Antibody O10 on Routinely Paraffin-embedded Samples
- Author
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Nicole Brousse, Philippe Gaulard, Laurence Boumsell, Sylvie Fraitag, Marie Laure Boulland, Marie-Catherine Voisin, Jean-François Emile, Elie-Serge Zafrani, Janine Wechsler, and Rita Cologon
- Subjects
Pathology ,medicine.medical_specialty ,Anticorps monoclonal ,medicine.diagnostic_test ,medicine.drug_class ,Biology ,medicine.disease ,Monoclonal antibody ,Paraffin embedded ,Pathology and Forensic Medicine ,Histiocytosis ,Mouse monoclonal antibody ,Langerhans cell histiocytosis ,Biopsy ,medicine ,Immunohistochemistry ,Surgery ,Anatomy - Abstract
The histological and immunohistochemical findings of 34 biopsy specimens from patients with Langerhans' cell histiocytosis (LCH) are reported, with special emphasis on the findings with CDIa mouse monoclonal antibody (MAb) O10 using paraffin-embedded material. Eighteen patients were treated in an ad
- Published
- 1995
41. Congenital abnormalities of the biliary tract
- Author
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Daniel Dhumeaux, Elie Serge Zafrani, Alain Luciani, and D. Cherqui
- Subjects
Ductal Plate Malformation ,Pathology ,medicine.medical_specialty ,business.industry ,Biliary tract ,Medicine ,business - Published
- 2012
42. Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study
- Author
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Jean-Pierre Bronowicki, Elie-Serge Zafrani, Armelle Poujol-Robert, François Bailly, Dominique Larrey, Marc Bourlière, Albert Tran, Marie-Christine Gelineau, Jérôme Guéchot, Hélène Voitot, Victor de Ledinghen, I. Hubert, Michel Vaubourdolle, Adeline Paris, Dominique Guyader, Nathalie Sturm, Jean-Charles Renversez, Jean-Luc Bosson, Jean-Pierre Zarski, Candice Trocme, Maria Alessandra Rosenthal-Allieri, Tarik Asselah, Renée-Claude Boisson, Frédéric Ziegler, Elisabeth Lasnier, Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hépatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et remodelage, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Service d'Hépato-Gastroentérologie, Hôpital St Joseph, Service de Biochimie et Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Hôpital Hôtel Dieu, French Clinical Biology Society (Société Francaise de Biologie Clinique), Association for Liver Research (l'Association pour l'Etude du Foie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], Université Nice Sophia Antipolis (... - 2019) (UNS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Service d'hépato- gastro-entérologie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Liver Cirrhosis ,Male ,Cirrhosis ,Transient elastography ,Biopsy ,MESH: Elasticity Imaging Techniques ,Chronic hepatitis C ,Gastroenterology ,MESH: Biopsy ,0302 clinical medicine ,Prospective Studies ,Prospective cohort study ,0303 health sciences ,Hematologic Tests ,MESH: Middle Aged ,medicine.diagnostic_test ,Hepatitis C ,Middle Aged ,MESH: Predictive Value of Tests ,3. Good health ,MESH: Hepatitis C, Chronic ,Liver biopsy ,Predictive value of tests ,Elasticity Imaging Techniques ,030211 gastroenterology & hepatology ,Female ,MESH: Liver Cirrhosis ,Adult ,medicine.medical_specialty ,Liver fibrosis ,MESH: Hematologic Tests ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,030304 developmental biology ,Surrogate markers ,Blood tests ,MESH: Humans ,Hepatology ,Receiver operating characteristic ,business.industry ,MESH: Adult ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Hepatitis C, Chronic ,medicine.disease ,MESH: Prospective Studies ,MESH: Male ,Surgery ,business ,MESH: Female - Abstract
International audience; BACKGROUND & AIMS: Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC). METHODS: This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4 mm). Performance was assessed using ROC curves corrected by Obuchowski's method. RESULTS: Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski's measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70-73% to 80-83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC's ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis. CONCLUSIONS: Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.
- Published
- 2012
43. Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats.: LPC aggravates liver CCl4-induced fibrosis
- Author
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Agnès Fourcot, Y. Laperche, Arthur Brouillet, Marie-Noële Chobert, Dominique Couchie, P. Mavier, Elie-Serge Zafrani, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université Paris-Est Marne-la-Vallée (UPEM), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by INSERM, University Paris-Est Creteil and Agence Nationale pour la Recherche (ANR-06-Physio-022-2)., and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Cirrhosis ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Antigens, Differentiation, Myelomonocytic ,Inflammation ,Liver Cirrhosis, Experimental ,Article ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,03 medical and health sciences ,TGFβ ,0302 clinical medicine ,Fibrosis ,Antigens, CD ,Transforming Growth Factor beta ,Acetylaminofluorene ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,epithelial-mesenchymal transition ,Molecular Biology ,Carbon Tetrachloride ,030304 developmental biology ,Keratin-19 ,0303 health sciences ,biology ,Stem Cells ,fibrosis ,liver progenitor cells ,Cell Biology ,Transforming growth factor beta ,2-Acetylaminofluorene ,medicine.disease ,Actins ,3. Good health ,Rats ,Cytokine ,Liver ,biology.protein ,030211 gastroenterology & hepatology ,medicine.symptom ,Hepatic fibrosis ,Transforming growth factor - Abstract
International audience; Hepatic fibrosis, the major complication of virtually all types of chronic liver damage, usually begins in portal areas, and its severity has been correlated to liver progenitor cells (LPC) expansion from periportal areas, even if the primary targets of injury are intralobular hepatocytes. The aim of this study was to determine the potential fibrogenic role of LPC, using a new experimental model in which rat liver fibrosis was induced by chronic carbon tetrachloride (CCl(4)) administration for 6 weeks, in combination with chronic acetylaminofluorene treatment (AAF), which promotes activation of LPC compartment. Treatment with CCl(4) alone caused a significant increase in serum transaminase activity as well as liver fibrosis initiating around central veins and leading to formation of incomplete centro-central septa with sparse fibrogenic cells expressing α-smooth muscle actin (αSMA). In AAF/CCl(4)-treated animals, the fibrogenic response was profoundly worsened, with formation of multiple porto-central bridging septa leading to cirrhosis, whereas hepatocellular necrosis and inflammation were similar to those observed in CCl(4)-treated animals. Enhanced fibrosis in AAF/CCl(4) group was accompanied by ductule forming LPC expanding from portal areas, αSMA-positive cells accumulation in the fibrotic areas and increased expression of hepatic collagen type 1, 3 and 4 mRNA. Moreover, CK19-positive LPC expressed the most potent fibrogenic cytokine transforming growth factor-β (TGFβ) without any expression of αSMA, desmin or fibroblast-specific protein-1, demonstrating that LPC did not undergo an epithelial-mesenchymal transition. In this new experimental model, LPC, by expressing TGFβ, contributed to the accumulation of αSMA-positive myofibroblasts in the ductular reaction leading to enhanced fibrosis but also to disease progression and to a fibrotic pattern similar to that observed in humans.
- Published
- 2012
44. Non-invasive assessment of liver graft fibrosis by transient elastography after liver transplantation
- Author
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Elie-Serge Zafrani, Fatiha Medkour, Catherine Douvin, Françoise Roudot-Thoraval, Jeanne Tran Van Nhieu, Daniel Cherqui, Christophe Duvoux, Calina Atanasiu, Camille Barrault, Ariane Mallat, and Michael D. Kluger
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Liver Cirrhosis ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Liver transplantation ,Gastroenterology ,Postoperative Complications ,Fibrosis ,Interquartile range ,Internal medicine ,Biopsy ,medicine ,Humans ,Prospective Studies ,Hepatology ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Liver Transplantation ,Transplantation ,Liver biopsy ,Hepatocellular carcinoma ,Elasticity Imaging Techniques ,Female ,Radiology ,business ,Transient elastography - Abstract
Liver stiffness measurement (LSM) by transient elastography (TE) (FibroScan) is a validated method of quantifying liver fibrosis in non-transplanted patients with hepatitis C virus (HCV). It could be useful in follow-up after liver transplantation (LT). The aim of this study was to assess the diagnostic accuracy of LSM in evaluating liver fibrosis after LT in patients with and without recurrent HCV.Forty-three patients (mean age 57.6 ± 9.9 years), 28 (65.1%) HCV-positive patients and 15 (34.9%) HCV-negative patients underwent gold standard liver biopsy and TE 55.8 ± 4.9 months after transplantation. Liver fibrosis was scored on biopsy specimens according to METAVIR (F0-F4). Accuracy of TE and optimal stiffness cut-off values for fibrosis staging were determined by a receiver-operating characteristics (ROC) curve analysis.Median stiffness values were significantly different for METAVIR score less than 2 (5.8 kPa) vs. METAVIR score greater to equal to 2 (9.6 kPa) (P0.001). The area under the ROC curve was 0.83 for METAVIR score greater to equal to 2 (95%CI: 0.71-0.95). The optimal stiffness cut-off value was 7 kPa for METAVIR scores greater to equal to 2. The results were similar whether the patients had recurrent HCV infection or not.These results indicate that transient elastography accurately identifies LT recipients with significant fibrosis, irrespective of HCV status. It is a promising non-invasive tool to assess graft fibrosis progression after LT in patients with HCV recurrence, as well as for screening of late graft fibrosis of other etiologies. Transient elastography could reduce the use of invasive protocol biopsies.
- Published
- 2011
45. Phase II study of sirolimus in treatment-naive patients with advanced hepatocellular carcinoma
- Author
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Emmanuel Itti, Christophe Duvoux, Anne Hulin, Françoise Roudot-Thoraval, Elie Serge Zafrani, Alexis Laurent, Alain Luciani, Thomas Decaens, and Ariane Mallat
- Subjects
Adult ,Liver Cirrhosis ,Male ,Mucositis ,medicine.medical_specialty ,Cirrhosis ,Carcinoma, Hepatocellular ,Phases of clinical research ,Kaplan-Meier Estimate ,Infections ,Gastroenterology ,Multimodal Imaging ,Therapy naive ,Pharmacokinetics ,Internal medicine ,Acne Vulgaris ,medicine ,Clinical endpoint ,Humans ,Fatigue ,Aged ,Sirolimus ,Hepatology ,business.industry ,TOR Serine-Threonine Kinases ,Liver Neoplasms ,Middle Aged ,medicine.disease ,Surgery ,Epistaxis ,Treatment Outcome ,Hepatocellular carcinoma ,Positron-Emission Tomography ,Toxicity ,Disease Progression ,Female ,business ,Tomography, X-Ray Computed ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Rapalogs are emerging as promising targeted anticancer drugs. Activation of the PI3K/Akt/mTOR pathway has been observed in 15–50% of hepatocellular carcinomas. Methods In this phase II study, patients with advanced hepatocellular carcinoma and underlying cirrhosis received sirolimus (20 mg/week for 1 month then 30 mg/week). Tumour response was assessed every 8 weeks. The primary endpoint was the objective tumour response rate according to the Response Evaluation Criteria in Solid Tumours criteria. Secondary endpoints included the objective response according to the modified Response Evaluation Criteria in Solid Tumours criteria, safety, and pharmacokinetic parameters. Results Twenty-five patients received sirolimus for a median of 20.6 weeks. Two patients had an objective response (8%, 95CI: 0.98–26.03), including one complete response, and 8 patients had stable disease. There were 2 cases of grade 5 toxicity (infections) and 5 cases of grade 3 toxicity. The main grade 1/2 toxicity was mild transient fatigue (76%). Median time to radiological progression and overall survival were 15.3 weeks (range: 8.2–173.9) and 26.4 weeks (range: 8.2–173.9) respectively. Use of the modified Response Evaluation Criteria in Solid Tumours criteria did not identify any further responders. Conclusion These data suggest that first-line sirolimus shows antitumoural efficacy in advanced hepatocellular carcinoma. Larger trials with Child A patients are needed.
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- 2011
46. Transplantation for liver failure in patients with sickle cell disease: challenging but feasible
- Author
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Monika, Hurtova, Dora, Bachir, Ketty, Lee, Julien, Calderaro, Thomas, Decaens, Michael D, Kluger, Elie Serge, Zafrani, Daniel, Cherqui, Ariane, Mallat, Frédéric, Galactéros, and Christophe, Duvoux
- Subjects
Adult ,Male ,Liver ,Humans ,Female ,Anemia, Sickle Cell ,Liver Failure, Acute ,Middle Aged ,Liver Transplantation - Abstract
Sickle cell disease (SCD) frequently affects the liver; if acute liver failure (ALF) develops, the only potentially effective therapeutic option is liver transplantation (LT). Only 12 patients for whom LT was performed for SCD-related ALF have been described so far. We report a retrospective series of 6 adult patients with SCD (3 men and 3 women, median age = 40.1 years) who underwent emergency LT. The indication for LT was ALF complicating cirrhosis in 5 patients (hepatitis C/iron overload-induced cirrhosis in 3 and iron overload-induced cirrhosis in 2); one patient had autoimmune hepatitis. The median follow-up was 52.7 months (0.5-123 months). The 1-, 3-, 5-, and 10-year survival rates were 83.3%, 66.7%, 44.4%, and 44.4%, respectively. One patient died of hepatocellular failure precipitated by hyperacute allograft rejection on post-LT day 10. Soon after LT, 2 patients developed seizures; in 1 case, the seizures were a complication of early calcineurin inhibitor-induced leukoencephalopathy. Four long-term survivors benefited from specific management of SCD; specifically, the hemoglobin S fraction was maintained below 30% and the total hemoglobin level was maintained between 8 and 10 g/dL. Two patients had mild vaso-occlusive crises. Three patients experienced a recurrence of hepatitis C virus (HCV) infection; 2 of these patients experienced reversible neurological complications while they were receiving antiviral treatment. Carefully selected patients with SCD may benefit from emergency LT. However, such patients seem to be particularly susceptible to neurological complications after LT. In contrast, severe SCD-related crises do not seem to recur if specific management is provided. Outcomes may be improved if the neurological complications can be minimized; for example, the administration of a calcineurin inhibitor can be delayed, and the management of HCV infection recurrence can be improved.
- Published
- 2011
47. Epstein-Barr Virus (EBV) Genomes and EBV-Encoded Latent Membrane Protein (LMP) in Pulmonary Lymphomas Occurring in Nonimmunocompromised Patients
- Author
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Jean-Christophe Sabourin, Marie-Claude Lescs, Elie Serge Zafrani, Panagiotis Kanavaros, Philippe Gaulard, Josette Brière, and Tony Petrella
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Male ,Herpesvirus 4, Human ,Pathology ,Lung Neoplasms ,medicine.disease_cause ,Lung Neoplasms/*immunology/microbiology/pathology ,immune system diseases ,hemic and lymphatic diseases ,Gammaherpesvirinae ,Antigens, Viral ,In Situ Hybridization ,Immunodeficiency ,Viral Matrix Proteins/*analysis ,Lymphoma, Non-Hodgkin ,Lymphoma, T-Cell/immunology/microbiology/pathology ,Middle Aged ,medicine.anatomical_structure ,RNA, Viral ,Immunohistochemistry ,Tumor Virus Infections/*immunology/pathology ,Anatomy ,Immunocompetence ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Biology ,Lymphoma, T-Cell ,Virus ,Herpesviridae ,Immunophenotyping ,Pathology and Forensic Medicine ,Viral Matrix Proteins ,Immunocompromised Host ,medicine ,Humans ,Lymphoma, B-Cell/immunology/microbiology/pathology ,neoplasms ,Aged ,Lung ,biology.organism_classification ,medicine.disease ,Epstein–Barr virus ,Lymphoma ,Tumor Virus Infections ,Antigens, Viral/*analysis ,RNA, Viral/analysis ,Lymphoma, Non-Hodgkin/*immunology/microbiology/pathology ,Surgery ,Herpesvirus 4, Human/*isolation & purification - Abstract
Recently, in situ hybridization (ISH) techniques have shown that Epstein-Barr virus (EBV) could be detected in tumor cells of most angiocentric T-cell non-Hodgkin's lymphomas (NHL). These studies included only a few cases of T-NHL of the lung and pulmonary B-NHL and have not been investigated. Furthermore, the expression of the EBV-encoded latent membrane protein (LMP), which is known for its oncogenic properties, has not been reported. Twelve pulmonary NHL (six angiocentric T-NHL and six B-NHL) arising in nonimmunocompromised patients were examined for the presence of EBV-EBER mRNAs and LMP with ISH and immunohistochemistry, respectively. Four cases of pulmonary lymphomas arising in immunocompromised patients were also included in the study for comparison (one T-NHL in a patient under immunosuppressive treatment and three B-NHL in AIDS patients). EBV-RNA and LMP were detected in tumor cells in two of six nonimmunocompromised angiocentric T-NHL and in the four immunocompromised NHL. The six nonimmunocompromised B-NHL were EBV negative. These results suggest that EBV is associated with some angiocentric pulmonary T-NHL arising in patients without overt immunodeficiency whereas it is absent in such patients with B-NHL. The presence of the transforming EBV-encoded LMP in tumor cells suggests that EBV may be involved in the pathogenesis of some pulmonary T-NHL. Am J Surg Pathol
- Published
- 1993
48. Immunolocalization of heparinbinding growth factors (HBGF) types 1 and 2 in rat liver. Selective hyperexpression of HBGF-2 in carbon tetrachloride-induced fibrosis
- Author
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Jean Rosenbaum, Frederic Charlotte, Khin Maung Win, Elie Serge Zafrani, Daniel Dhumeaux, Anne-Marie Preaux, and Philippe Mavier
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Male ,Pathology ,medicine.medical_specialty ,CCL4 ,Biology ,Liver Cirrhosis, Experimental ,digestive system ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,Fibrosis ,medicine ,Animals ,Carbon Tetrachloride ,Cellular localization ,medicine.disease ,Immunohistochemistry ,Rats ,Cell biology ,Fibroblast Growth Factors ,Liver ,chemistry ,Carbon tetrachloride ,Hepatic stellate cell ,Fibroblast Growth Factor 1 ,Fibroblast Growth Factor 2 ,Hepatic fibrosis - Abstract
Ito cells play a major role in liver fibrosis but the mechanisms controlling their activation in vivo are poorly understood. Heparin-binding growth factors (HBGF) types 1 and 2 are mitogenic for cultured Ito cells. They have been found in liver extracts but their cellular localization is unknown. We have studied by immunohistochemistry HBGF-1 and -2 expression in normal rat liver and in carbon tetrachloride (CCl4)-induced fibrosis. In normal liver, HBGF-1 was present only in sinusoidal cells whereas HBGF-2 was also detected in endothelial cells lining major vessels. At the acute stage of CCl4 intoxication, HBGF-2 was expressed in centrilobular clusters of mononuclear phagocytes that were surrounded by many HBGF-2-negative Ito cells. In the later stages, HBGF-2 was expressed by Ito cells within the fibrous bands. No modulation of HBGF-1 expression was noted at any stage. These results suggest that (1) at the acute stage of CCl4 intoxication, HBGF-2 produced by mononuclear phagocytes could participate in the recruitment of Ito cells; and (2) during the CCl4-induced fibrotic process, HBGF-2 could contribute to Ito cell proliferation and the synthesis of fibrosis components. In this in vivo model of hepatic fibrosis, the hyperexpression of HBGF-2 is a relatively specific event since the expression of a structurally related molecule, HBGF-1 was not modulated.
- Published
- 1993
49. Hepatocellular carcinoma and nodular regenerative hyperplasia after chemotherapy for metastatic colorectal carcinoma
- Author
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Daniel Azoulay, Elie-Serge Zafrani, and Julien Calderaro
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Organoplatinum Compounds ,Colorectal cancer ,medicine.medical_treatment ,Antineoplastic Agents ,Folic Acid ,Drug Therapy ,Internal medicine ,medicine ,Hepatectomy ,Humans ,Vascular Diseases ,Chemotherapy ,Hyperplasia ,Hepatology ,business.industry ,Liver Neoplasms ,Middle Aged ,medicine.disease ,Oxaliplatin ,Liver ,Hepatocellular carcinoma ,Cancer research ,Fluorouracil ,Colorectal Neoplasms ,business ,Nodular regenerative hyperplasia - Published
- 2014
50. P892 PREVALENCE OF DONOR SPECIFIC ANTIBODIES IN LIVER TRANSPLANTATION RECIPIENTS WITH UNEXPLAINED LIVER GRAFT ABNORMALITIES IS SIGNIFICANTLY HIGHER THAN IN CONTROL GROUPS
- Author
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C. Suberbielle, M. Carmagnat, Elie-Serge Zafrani, A. Mallat, Cyrille Feray, A. Ghandir, Christophe Duvoux, D. Desvaux, Françoise Roudot-Thoraval, and Monika Hurtova
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Liver graft ,Pathology ,medicine.medical_specialty ,Hepatology ,business.industry ,medicine.medical_treatment ,Donor specific antibodies ,medicine ,Liver transplantation ,business - Published
- 2014
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